Weiss Alexander, Ding Yuchuan
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, USA.
Cerebrovasc Dis. 2025 Jul 3:1-10. doi: 10.1159/000547092.
Stroke remains a leading cause of disability and death worldwide. While reperfusion therapies such as tissue plasminogen activator and mechanical thrombectomy have significantly improved stroke management, their effectiveness is limited by ischemia/reperfusion injury, which disrupts the blood-brain barrier (BBB), increases neuroinflammation, and exacerbates secondary neuronal damage. Consequently, there is an urgent need for adjunctive therapies that specifically target these secondary injury mechanisms.
This review explores novel therapeutic strategies aimed at mitigating neuroinflammation, poststroke edema, and BBB permeability. Key approaches discussed include anti-inflammatory therapies targeting tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and matrix metalloproteinases (MMPs); neuromodulation by vagus nerve stimulation (VNS); and the inhibition of edema-related molecules such as sulfonylurea receptor 1 (SUR1), aquaporin-4 (AQP4), and both systemic and peripheral hypothermic cooling. While these therapies show promise in preclinical models, their clinical translation is hindered by challenges such as systemic immunosuppression, susceptibility to infection, and limited therapeutic windows. Among these therapies assessed, SUR1 inhibition and remote administration of hypothermia (RAH) are promising candidates for improving stroke outcomes.
Secondary injury from BBB disruption, inflammation, and edema remains a major barrier to optimal stroke recovery. Pharmacologic, neuromodulatory, and molecular-targeting strategies, including TNF-α, IL-6, MMP inhibition, VNS, and hypothermia, each offer distinct therapeutic mechanisms, but face critical clinical translation barriers. Among emerging therapies, RAH and SUR1 inhibition represent novel interventions that address many of the translational challenges of other therapies by addressing key mechanisms of neuroinflammation and edema with favorable safety profiles.
中风仍然是全球残疾和死亡的主要原因。虽然组织纤溶酶原激活剂和机械取栓等再灌注疗法显著改善了中风治疗，但它们的有效性受到缺血/再灌注损伤的限制，这种损伤会破坏血脑屏障（BBB），增加神经炎症，并加剧继发性神经元损伤。因此，迫切需要针对这些继发性损伤机制的辅助疗法。
本综述探讨了旨在减轻神经炎症、中风后水肿和血脑屏障通透性的新型治疗策略。讨论的关键方法包括针对肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和基质金属蛋白酶（MMPs）的抗炎疗法；迷走神经刺激（VNS）进行神经调节；以及抑制与水肿相关的分子，如磺脲类受体1（SUR1）、水通道蛋白4（AQP4），还有全身和外周低温冷却。虽然这些疗法在临床前模型中显示出前景，但它们的临床转化受到全身免疫抑制、感染易感性和治疗窗口有限等挑战的阻碍。在评估的这些疗法中，SUR-1抑制和远程低温治疗（RAH）是改善中风预后的有希望的候选方法。
血脑屏障破坏、炎症和水肿导致的继发性损伤仍然是中风最佳恢复的主要障碍。药理学、神经调节和分子靶向策略，包括TNF-α、IL-6、MMP抑制、VNS和低温治疗，各自提供了独特的治疗机制，但面临关键的临床转化障碍。在新兴疗法中，RAH和SUR1抑制代表了新的干预措施，通过解决神经炎症和水肿的关键机制并具有良好的安全性，应对了其他疗法的许多转化挑战。
